OBJECTIVE: Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarrhythmia and whether time to treatment was related to outcome. METHODS: The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarrhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or “other.” Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models. RESULTS: One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040). SIGNIFICANCE: Greater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

The American Academy of Neurology and Child Neurology Society practice parameter published in 2004 (updated in 2012) concluded that adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) should be considered standard treatments for infantile spasms; there was insufficient evidence to support use of other agents1,2. An update to these guidelines may be needed in light of newly published data including the study cited above.

The National Infantile Spasms Consortium (NISC) recruited 230 children with infantile spasms from 22 US centers in a prospective study to assess early and sustained response to hormonal treatments (ACTH, oral steroids), VGB, and other treatments designated as nonstandard therapy3,4. Unlike the United Kingdom Infantile Spasm Study (UKISS), children with tuberous sclerosis (TS) were not excluded5. Dosing recommendations were provided for high-dose ACTH 150 units/m2 for 2 weeks followed by a rapid taper over 2 weeks, prednisolone 40 mg/day for 2 weeks followed by taper over 2 weeks and VGB 50 mg/kg/day for 3 days, 100 mg/kg/day for 3 days, and then 150 mg/kg/day for an unspecified duration. Patients were not randomized, so their doctors could select which treatment and dose to use; dosing guidelines were followed in 80/96 (83%) children who received ACTH compared with 34/50 (68%) for prednisolone and 32/41 (78%) for VGB. Response was judged by cessation of spasms at 2 weeks and resolution of hypsarrhythmia at 3 months.

Ninety-one of 198 (46%) of children receiving standard therapy responded versus only 3/32 (9%) of those who received nonstandard therapy. Response was seen in 53/97 (55%) of those received ACTH, 21/54 (39%) of those received prednisolone, and in 17/47 (36%) of those who received VGB. Response was higher for those with unknown etiology and normal development; however, children with mild or no developmental issues were more often prescribed ACTH, whereas those with severe impairments were often prescribed nonstandard treatments. Infants did not undergo formal developmental assessment. Relapse rate was highest in the oral steroid group (38%) versus other groups (18%). A trend toward higher response rates for high-dose ACTH was seen compared with low/intermediate dose ACTH but the study was not sufficiently powered to detect differences between these groups. Response was higher in children without structural lesions and normal development or mild delay (59%) versus those with genetic etiology (38%) or structural lesions (38%). Children with TS received mostly VGB; 5/8 (63%) children responded to VGB; the other 3 (38%) did not respond to ACTH (1; 13%) or nonstandard treatments (2; 25%).

A second paper from this same study evaluated response to a second treatment with a different drug in 118/136 (87%) subjects failing their first treatment who could be evaluated. In those treated with a second standard treatment, 27 of 49 (55%) responded. In contrast, only 17/69 (25%) of those treated with nonstandard therapy responded, a statistically significant difference (P < 0.001)4. Children receiving their first treatment within 4 weeks of spasm onset responded more favorably to their second drug than those treated later (36/82 (44%) versus 8/34 (24%), P = 0.040). Overall, 44/118 (37%) patients responded to the second treatment. Response rates were much higher in 10/18 (56%) children who received steroids (ACTH or prednisolone) or 17/31 (55%) of children who received VGB compared to 8/32 (25%) who received nonstandard treatments (p<0.001). Therefore, approximately half the children with IS are expected to respond to their first standard treatment and just over one-third (37%) to their second standard treatment. Altogether 150/230 (65%) of children in this cohort responded to their first or second treatment. Etiology and developmental status did not influence response to the second treatment.

Notwithstanding the non-randomized design and observational nature of this study, a large number of children were studied, so some useful conclusions can be drawn:

Standard treatments (ACTH, steroids, and VGB) are superior to nonstandard treatments and should be the preferred initial treatment for infantile spasms;

Hormonal treatments (ACTH, oral steroids) are superior to VGB except in children with TS for whom VGB is clearly more effective. Response to ACTH was higher than for VGB and also somewhat higher than oral steroids. Similar findings emerged from the UKISS trial favoring hormonal treatments over VGB after 14 days of treatment although this difference was not evident at 14 months5,6. Infants with cryptogenic etiology receiving hormonal treatment had higher developmental scores than those receiving VGB;

The NISC studies were not sufficiently powered to detect differences between various nonstandard treatments3,4. Published reports suggest that some therapies (ketogenic diet, valproate, topiramate) may be more effective than others such as phenobarbital, oxcarbazepine, or pyridoxine (at least in North America);

Response to a second standard treatment with different mechanism of action was superior to response to a second treatment with a similar mechanism of action.4;

A shorter time (<4 weeks) to starting standard treatment is associated with a higher response to the second therapy, suggesting that the window for optimal seizure control starts to close somewhere between 4 and 8 weeks after spasm onset4,6,7.

An interesting open-label trial published earlier this year by the International Collaborative Infantile Spasms Study (ICISS) recruited 766 children with infantile spasms from 102 hospitals in 5 countries7. The 377 children who met inclusion criteria (reasons for exclusion were not recorded) were randomly assigned 1:1 to receive either hormonal therapy alone or hormonal therapy with VGB. Cessation of spasms occurred in 133/186 (72%) of those assigned to a combination of hormonal treatments with VGB versus 108/91(57%) of those receiving hormonal treatment alone (p=0.002). Infants receiving combination therapy also had a significantly shorter time to cessation of spasms (p<0.001). These results indicate that some infants clearly respond better to combination therapy than to hormone treatment alone. given the urgency of fully controlling spasms, combination treatment may be ideal as response rates dropped in those initiating treatment greater than 2 months after spasm onset. A limitation of this study was the large proportion of infants who were excluded from the study and the failure to randomize the type of hormonal treatment used. (parents could choose between tetracosactide depot or prednisolone). However, the group receiving tetracosactide had greater electroclinical response than the prednisolone group. These results need to be replicated before tetracosactide can be recommended over prednisolone.

Oral steroids are a reasonable option in certain situations (socioeconomic, parental educational level and choice) but doses greater than or equal to 2 mg/kg/day are needed. A 2012 review of available data concluded that the efficacy of high-dose corticosteroids was similar to low-dose ACTH and inferior to high-dose ACTH8.

Using a standardized management protocol for treating infantile spasms can improve response rates to treatment; after its implementation at a single institution, remission rates more than doubled9. Use of natural ACTH gel is preferred in the United States, whereas synthetic tetracosactide depot is used in the rest of the world. Given the very high cost of natural ACTH gel (ACTHAR) it would be helpful to compare these two formulations.